CA1117029A - Filtration apparatus for separating blood cell-containing liquid suspensions - Google Patents
Filtration apparatus for separating blood cell-containing liquid suspensionsInfo
- Publication number
- CA1117029A CA1117029A CA000328013A CA328013A CA1117029A CA 1117029 A CA1117029 A CA 1117029A CA 000328013 A CA000328013 A CA 000328013A CA 328013 A CA328013 A CA 328013A CA 1117029 A CA1117029 A CA 1117029A
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- Prior art keywords
- filtration
- membrane
- suspension
- flow
- flow channels
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000001914 filtration Methods 0.000 title claims abstract description 105
- 239000006194 liquid suspension Substances 0.000 title claims abstract description 13
- 210000000601 blood cell Anatomy 0.000 title abstract description 14
- 239000012528 membrane Substances 0.000 claims abstract description 78
- 239000000725 suspension Substances 0.000 claims abstract description 42
- 239000000706 filtrate Substances 0.000 claims abstract description 34
- 210000004369 blood Anatomy 0.000 claims abstract description 29
- 239000008280 blood Substances 0.000 claims abstract description 29
- 238000000926 separation method Methods 0.000 claims abstract description 13
- 239000007788 liquid Substances 0.000 claims abstract description 7
- 238000011144 upstream manufacturing Methods 0.000 claims abstract description 6
- 210000004379 membrane Anatomy 0.000 claims description 72
- 230000001413 cellular effect Effects 0.000 claims description 31
- 239000012982 microporous membrane Substances 0.000 claims description 6
- 230000006872 improvement Effects 0.000 claims description 5
- 102000004506 Blood Proteins Human genes 0.000 claims description 4
- 108010017384 Blood Proteins Proteins 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 25
- 238000002616 plasmapheresis Methods 0.000 abstract description 11
- 239000002577 cryoprotective agent Substances 0.000 abstract description 7
- 238000002360 preparation method Methods 0.000 abstract description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 7
- 230000004907 flux Effects 0.000 description 6
- 239000006285 cell suspension Substances 0.000 description 5
- 230000000875 corresponding effect Effects 0.000 description 5
- 210000003743 erythrocyte Anatomy 0.000 description 5
- 239000011148 porous material Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 206010018910 Haemolysis Diseases 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000005194 fractionation Methods 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 210000001772 blood platelet Anatomy 0.000 description 2
- 239000008151 electrolyte solution Substances 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000013536 elastomeric material Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000005534 hematocrit Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- -1 polypropylene Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/49—Blood
- G01N33/491—Blood by separating the blood components
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Hematology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Urology & Nephrology (AREA)
- Ecology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- External Artificial Organs (AREA)
- Separation Using Semi-Permeable Membranes (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A filtration device for effecting separation of a blood cell-free liquid filtrate from a blood cell-containing liquid suspension in continuous laminar flow therethrough, employing a microporous filtration membrane. The filtration flow channels along the surface of the upstream side of the membrane wall are provided with a width across the membrane wall surface which gradually and uniformly increases from the inlet end to the outlet end of the flow channel, whereby the membrane wall shear rate of the suspension in laminar flow through the flow channel will gradually and uniformly vary along the length of the flow channel from a maximum value at its inlet end to a minimum value at its outlet end. Such variation in shear rate corresponds with the variation in the transmembrane pressure conditions along the length of the flow channel so as to enable better control of the filtration operating conditions to ensure optimal filtration rates per area of membrane without damage to the blood cells. Useful applications of the device include the separation of plasma from whole blood in a continuous flow plasmapheresis procedure, and the removal of cryoprotective agents from previously frozen, thawed preparations of blood cells.
A filtration device for effecting separation of a blood cell-free liquid filtrate from a blood cell-containing liquid suspension in continuous laminar flow therethrough, employing a microporous filtration membrane. The filtration flow channels along the surface of the upstream side of the membrane wall are provided with a width across the membrane wall surface which gradually and uniformly increases from the inlet end to the outlet end of the flow channel, whereby the membrane wall shear rate of the suspension in laminar flow through the flow channel will gradually and uniformly vary along the length of the flow channel from a maximum value at its inlet end to a minimum value at its outlet end. Such variation in shear rate corresponds with the variation in the transmembrane pressure conditions along the length of the flow channel so as to enable better control of the filtration operating conditions to ensure optimal filtration rates per area of membrane without damage to the blood cells. Useful applications of the device include the separation of plasma from whole blood in a continuous flow plasmapheresis procedure, and the removal of cryoprotective agents from previously frozen, thawed preparations of blood cells.
Description
1117(~29 BACKGROUND OF THE INVENTION
This invention relates to a fractionation of blood cell-containing liquid suspensions and, re particularly, to an apparatus for effecting such fractionation by filtration through a microporous membrane.
Certain highly desirable blood processing procedures require the ability to effect an efficient separation of a liquid suspension of blood cellular components into a cellular component-containing fraction and a cellular component-free liquid fraction without causing damage to the cellular components. For example, the preservation of red blood cells, white blood cells or platelets which have been separated from whole blood for future use in trans}usions, can be effectively achieved by freezing a prepared suspension of the blood cells in an electrolyte solution containing a suitable concentration of a cryoprotective agent, such as glycerol or dimethyl sulfoxide. Since the c~ncentration of the cryoprotective agent required for the freezing procedure is well above physiologically tolerable levels, the prepared blood cell suspension must be fractionated subsequent to thawing and prior to use so as to ~emove the cryoprotective agent therefrom or at least to reduce its concentration in the suspension to a physiologically tolerable level. Two techniques are currently available ~ for effecting such fractionation, one baæed upon the ; reversible agglomeration of blood cells in the presence of carbohydrates, and the other upon various centrifu-r ~1~7029
This invention relates to a fractionation of blood cell-containing liquid suspensions and, re particularly, to an apparatus for effecting such fractionation by filtration through a microporous membrane.
Certain highly desirable blood processing procedures require the ability to effect an efficient separation of a liquid suspension of blood cellular components into a cellular component-containing fraction and a cellular component-free liquid fraction without causing damage to the cellular components. For example, the preservation of red blood cells, white blood cells or platelets which have been separated from whole blood for future use in trans}usions, can be effectively achieved by freezing a prepared suspension of the blood cells in an electrolyte solution containing a suitable concentration of a cryoprotective agent, such as glycerol or dimethyl sulfoxide. Since the c~ncentration of the cryoprotective agent required for the freezing procedure is well above physiologically tolerable levels, the prepared blood cell suspension must be fractionated subsequent to thawing and prior to use so as to ~emove the cryoprotective agent therefrom or at least to reduce its concentration in the suspension to a physiologically tolerable level. Two techniques are currently available ~ for effecting such fractionation, one baæed upon the ; reversible agglomeration of blood cells in the presence of carbohydrates, and the other upon various centrifu-r ~1~7029
2 -gation proce~ures.
The problems associated with the removal ofcryoprotective agents has been one of the major obstacles standing in the way of re extensive clinical use of frozen cells.
In the field of red cell freezing, various advantages have been cited for pro ting the use of this product. They include a possible reduction in hepatitis transmission, a reduction in transmission of undesirable antigens and antibodies, and most important, a prolonged storage period permitting accumulation of ~rare red cells" blood for autologous transfusion, and stockpiling for use during shortages. Current technology can be used to achieve these goals but a more simple and efficient system is needed.
Platelets frozen storage is desirable in order to reduce outdating and allow for provisions of ~matched~
or autologous cells. Techniques currently in use are not satisfactory and the microporous system may be suitable for such an application. Similarly, white cell storage is a problem ~nd transfusion of unfrozen products are still basically experimental. However, it is expected that utilization will increase, and that frozen storage will be needed for their efficient 2S management.
Another highly desirable blood processing procedure involving the separation of a liquid suspension of blood cellular components into a cellular component-containing fraction and a cellular component-free liquid fraction, is plasmapheresis. Plasmapheresis is defined as the process of removal of whole blood from the body of a blood donor by venesection, separation of its plasma portion, and reintroduction of the cellular portion into the donor's bloodstream. The cell-free plasma thus collected may either be used directly for patient care or ~urther processed into specific plasma derivatives for clinical use. The return of the cellular components to the donor provides this plasma 1117~2~
,~
collection procedure with the advantage that it enables donations by the donor at more frequent intervals. In addition to its use for plasma collection, plasmapheresis also has therapeutic implications in plasma exchange procedures for the treatment of various clinical disorders.
Currently, the most efficient and commonly employed techniques for carrying out the plasmapheresis procedure utilize "batchncentrifugation systems for effecting the separation of the cell-free plasma from the whole blood.
The most serious drawback with these currently used techriques is the relatively long period of donor time which they require, typically ranging from one to one-and-a-half hours or re for collecting 500 ml of cell-free pla~ma. Such long period of donor time tends tohave a detrimental effect upon the recruitment of volunteer donors and upon the overall cost-effectiveness of the plasmapheresis procedure.
Techniques for the separation of cell-free plasma from whole blood by filtration through a microporous membrane have previously been proposed. For example, in U. S. Patent No. 3,705,100, issued ~ecember 5, 1972, to Blatt, et al, there is disclosed a blood fractionating process and apparatus wherein whole blood is conducted in laminar flow across the surface of a microporous membrane along a flow path which is substantially parallel to the upstream side of the membrane under pressure conditions at the inlet and outlet ends of the flow path sufficient to maintain the laminar flow and to provide a filtration driving force from the upstream side to the downstream side of the membrane. Cell-free plasma is recovered as filtrate from the downstream side of the membrane, and the cellular component-containing fraction is recovered from the outlet end of the flow path. The patent teaches that one embodiment of the process and apparatus disclosed therein is capable of separating approximately 3.0 to 3.4 ml of plasma from a 10 ml sample of fresh blood of normal hematocrit in a filtering r ~117(~9 time of 15 to 20 minutes. While such filtering capacity may be adequate for the in vitro processing of relatively s~all amounts of plasma for subsequent physical, chemical or clinical analyses, it obviously would not be sufficient for practical utility in plasmapheresis, where the objective is to collect 500 ml of cell-free plasma in certainly no greater and preferably substan-tially less than the 60 to 90 minutes required by the standard plasmapheresis techniques.
In attempting to scale up the filtration process and apparatus disclosed in the Blatt, et al patent to a filtration capacity sufficient for practical utility in carrying out the plasmaphere~is procedure~ a number of interrelated factors must be taken into consideration.
First of all, in order to minimize the total required membrane area so that the resulting filtration dule will be reaRonably compact in size, and in order to-minimize the required period of donor time, it is most desirable to operate under conditions which will provide optimal filtrate flux, i.e., filtration rate per area of membrane.
Since, in certain cases, the filtrate flux will be governed primarily by the transmembrane pressure, i.e., the pressure differential between the upstream and downstream sides of the membrane providing the filtration driving force, the transmembrane pressure should be maintained sufficiently high so as to maximize the filtrate flux. However, too high a transmembrane pressure will cause the blood cellular components to be forced to the membrane surface and interact therewith, leading to irreversible damage or hemolysis of the cells or possibly even to plugging of the membrane pores.
Proper control of the transmembrane pressure so as to provide optimal filtration rate per area of membrane without causing damage to the cellular components is further complicated by the pressure drop from the inlet end to the outlet end of the blood flow path, which causes corresponding variations in the transmembrane pressure through the system. A relatively high pressure l.~i702~
drop could lead to a very low transmembrane pressure in the outlet region. Thus, in order to insure that the transmembrane pressure in the outlet region will be maintained sufficiently high for efficient operation, the transmembrane pressure in the inlet region must be correspondingly higher so as to compen-sate for the pressure drop thxough the system. Moreover, if the system is to be used for carrying out a truly continuous flow plasmapheresis procedure wherein the cellular component-containing fraction exiting from the outlet end of the filtra-tion flow path is directly reinfused into the donor's bloodstream,a further factor influencing the transmembrane pressure through the system is the requirement that the pressure at the outlet end of the filtration flow path be at least sufficient to over-come the sum of the return venous blood pressure and the pressure drop in the return needle and tubing assembly if an accessory blood pump is to be avoided.
An improvement in the filtration process is described in the aforementioned Blatt, et al patent. This improvement consists of controlling the membrane wall shear rate of the suspension along the filtration flow path so that such shear rate will be sufficiently high to cause axial migration of cells and inhibit interactions of the cellular components with the membrane surface at the particular transmembrane pressure conditions employed and sufficiently low so as not to itself induce mechanical lysis or damage to the cellular components.
It was found that by properly ,,.-, .. .
correlatin~ the membrane wa.ll shear rate with the particular set of transmembrane pressure conditions employed, it is possible to operate at transmembrane pressures providing optimal filtration - 5a -111~1)2~9 rate per area of membrane while at the same time inhibiting lysis-cau~ing interractions of the cellular components with the membrane surface which would othex-wise occur at lower membrane wall shear rates. As disclosed in said co-pending Friedman, et al application, such improvement enables the filtration process to be scaled up to a filtration capacity rendering it practical for use as the blood separation technique in a continuous flow plasmapheresis system, requiring a substantially shorter period of donor time than that required by the standard centrifugal techniques conventionally employed for this purpose; and furthermore `
broadens the applicability of the filtration process to also render it a relatively simple, efficient and economical technique for effecting removal of cryopro-tective agent from a previously frozen, thawed preparation of blood cells.
As disclosed in said co-pending Friedman, et al application, the membrane wall shear rate of the blood cell-containing liquid suspension along the filtration flow path is a function of both the inlet suspension flow rate and the filtration flow channel dimensions, increasing with increasing flow rates.and/or.decreasing flow cha~nel dimensions. Thus, once the operating membrane wall shear rate has been determined so as to be properly correlated with the transmembrane pressure conditions being employed to provide optimal filtrate flux without damage to the cellular components, such shear rate can be achieved by proper coordination of the inlet suspension flow rate with the filtration flow channel dimensions.
SUMMP.RY OF THE INVENTION
It is, accordingly, a primary object of the present invention to provide an improved filtration apparatus which is specifically designed for use in effectively carrying out the improved filtration process described and claimed in the aforementioned co-pending Friedman, .
1117~%9 et al applicatlon.
Another object of the invention is to provide a filtra-tion apparatus in accordance with the preceding object, which facilitates correlation of the membrane wall shear rate of the liquid suspension flowing therethrough with the transmembrane pressure conditions existing therein along the entire length of the filtration flow path.
The preferred embodiment of the filtration apparatus dis-closed herein has a reasonably compact size and a filtering capa-city sufficient to provide 500 ml of cell-free plasma filtrate from whole blood in approximately 30 minutes. The preferred appa-ratus has a filtering capacity sufficient to reduce the glycerol concentration in a unit of previously frozen, thawed glycerol-containing red blood cell preparation from a cryoprotectively effective level to a physiologically tolerable level in approxi-mately 30 minutes.
The present invention provides a filtration apparatus designed so that the membrane wall shear rate of a blood cell-containing liquid suspension in continuous laminar flow under pressure therethrough will vary along the length of the filtration flow path in the same manner as the transmembrane pressure, i.e.
from a maximum value at the inlet end of the filtration flow path to a minimum value at the outlet end thereof, thereby faci-litating correlation of the membrane wall shear rate with the transmembrane pressure conditions along the entire length of the filtration flow path so as to insure optimal filtrate flux with-out damage to the cellular components.
In accordance with the present invention there is provided in a filtration apparatus for effecting separation of a cellular component-free liquid filtrate from a liquid suspension of blood ~L17025'~
cellular components in continuous laminar flow under pressure through the apparatus by filtration through a microporous mem-brane which is permeable to blood proteins and impermeable to blood cellular components, comprising a housing means provided with a suspension inlet port and a suspension outlet poxt, the suspension inlet port leading into the inlet end of at least one continuous suspension flow channel which extends within the housing means and terminates at its outlet end in the suspension outlet port, each flow channel having one of its walls formed of a microporous filtration membrane disposed within the housing means, whereby the flow channel defines a filtration flow path along the surface of the upstream side of its membrane wall, the microporous filtration membrane being permeable to blood proteins and impermeable to blood cellular components and the housing means being further provided with a filtrate exit port disposed on the downstream side of the membrane wall, the improvement con-sisting of each of the flow channels having a width across the surface of its membrane wall which gradually and uniformly in-creases along the length thereof from its inlet end to its outlet end, each said channel being constructed and arranged so that the membrane wall shear rate of the suspension flowing along the filtration flow path will gradually and uniformly vary along the length of the flow channel from a maximum value at the inlet end to a minlmum value at the outlet end.
The filtration apparatus preferably includes a plurality of such flow channels of diverging width design in spaced parallel relation to each other across the surface of a single micro-porous filtration membrane, whereby spaced portions of the mem-brane constitute the respective membrane walls of the parallel flow channels. An inlet flow distributor means connects the res-0~9 pe~t~ nlet ellds of the parallel flow channels to the suspen-sion inlet port, and an outlet flow collector means connects the respect:ive outlet ends of the parallel flow channels to the sus-pension outIet port. A filtrate collector means disposed on the downstream side of the membrane walls collects and conducts to the filtrate exit port the filtrate passing through the respective membrane walls of the parallel flow channels. In its preferred embodiment, the filtration apparatus includes first and - 8a -0~
9 _ second microporou~ filtration m~mbranes in spaced parallel relation to each other, and fir~t and second sets of parallel spaced flow channels disposed between the two membranes, so that spaced portions of the first membrane constitute the respective membrane walls of the parallel flow channels of the first set, and spaced portions of the second membrane constitute the respective membrane walls of the parallel flow channels of the second set.
BRIEF DESCRIPTION OF THE DRAWINGS
Other features and advantages of the present invention will be apparent from the following detailed description of preferred embodiments accompanied by the attached drawings, in which: ¦
Figure 1 is a perspective view of a filtration module designed in accordance with the present invention in its assembled form;
Figure 2 is an exploded view in perspective with cutaway portions showing the component members of the filtration module of Figure l;
Figure 3 is an enlarged top view, partly in section, of the bottom outer plate member of the filtration module shown in Figure 2;
Figure 4 is a sectional view of the bottom outer plate member of the filtration module taken along the line 4-4 of Figure 3;
Figure 5 is a sectional view of the bottom outer plate member of the filtration module taken along the line 5-5 of Figure 3;
Figure 6 is an enlarged sectional view of the assembled filtration module taken along the line 6-6 of Figure l; and Figure 7 is an enlarged fragmented sectional view of the assembled filtration module taken along the line 7-7 of Figure 1.
)2~31 - 10 - i DESCRIPTION OF PREFERRED EMBODIMENTS
Referring now to Figure 1 of the drawings, a filtration module 10 in accordance with the present invention is shown in its preferred embodiment as 5 comprising a rectangular housing formed of a central core member 12 disposed between identical top and bottom outer plate members 14. The central core member 3 12 is provided at its one end with a suspension inlet port 16 leading into the housing, and at its other end 10 with a suspension outlet port 18 leading out of the housing.
Referring now to Figure 2, the suspension inlet port 16 is shown as leading into an inlet distributor channel 20 extending within the central core member 12 15 partially across its width. A plurality of inlet flow passages 22 spaced across the width of the central core member 12 lead from the inlet distributor channel 20 to the upper and lower surfaces of the central cor~
member 12. As shown, there are six such passages 22~
20 three leading to the upper surface and three to the lower surface of the central core member 12. At its opposite end, the central core member 12 is provided with six similarly arranged outlet flow passages 24 leading from its upper and lower surfacec into an outlet collector 25 channel 26 which extends within the central core member 12 partially across its width and leads into the suspension outlet port 18. The outlet flow passages 24 have a wider cross section than the inlet flow passages 22.
Identical upper and lower gasket members 28 are disposed over the upper and lower surfaces, respectively, of the central core member 12. The gasket members 28 are formed of a suitable elastomeric material, such as silicone rubber, and are provided with three lengthwise extending, transversely spaced, cut-out portions 30, each of which is positioned to extend over the surface of the central core member 12 from one of the inlet flow ,.
1~1702!~
passages 22 to the corresponding outlet flow passage 24. The width of each cut-out portion 30 gradually and uniformly increases along the length thereof from the inlet flow passage 22 to the outlet flow passage 24, its width at each end correspon-ding to the cross sectional width of the respective flow passage.
In the preferred embodiment of the filtration module in accordance with the present invention, the ratio of the width of the cut-out portion 30 at its outlet flow passage end to that at its inlet flow passage end is approximately 2:1.
The upper and lower gasket members 28 are covered, respectively, with identical upper and lower microporous filtra-tion membrane members 32. Such microporous membranes are known filter materials having holes of controlled shape and size running through their thickness and capable of effecting separation of very small particulate or molecular components from suspensions or solutions. Such microporous membranes are commercially available in various pore sizes. For example, poly-carbonate microporous membranes are commercially available under the trademark "Nuclepore" from the Nuclepore Corporation, and cellulosic ester microporous membranes are commercially available from Millipore Corporation. Suitable pore sizes found effective for filtering cell-free plasma from whole blood or cryoprotective agent from previously frozen, thawed blood cell suspensions, range broadly from about 0.2 to about 1.5 microns in diameter, and preferably from about 0.40 to about 0.60 microns in diameter.
The upper and lower microporous filtration membrane members 32 are covered, respectively, with the top and bottom outer plate members 14 which, in their surface facing the microporous filtration membrane member, are each provided with three lengthwise extending, transversely spaced wells 34, which correspond in shape, size and relative position with the cut-out portions 30 of the gasket members 28. The bottom wall of each well 34 is provided with a plurality of flat-surfaced ridges 36 form:Lng a network of filtrate collector grooves 38. Into each well 34 is inserted a macroporous support member 40, for example, formed of sintered polypropylene. The macroporous support members 40 are shaped and dirnensioned so as to rest upon the ridges 36 of its corresponding well 34 and completely fill the well above the network of filtrate collector grooves 38.
The structure of the outer plate members 14, without the macroporous support members 40 inserted therein, is more clearly shown in Figures 3 to 5. The network of filtrate collector grooves 38 formed by the ridges 36 on the bottom wall of each well 34 empties through a respective filtrate flow passage 42 into a filtrate collector channel 44 which extends transversely within the outer plate member 14 midway along its length. The filtrate collector channel 44 terminates in a filtrate outlet port 46.
The central core member 12, the upper and lower gasket members 28, the upper and lower microporous filtration membrane members 32, and the top and bottom outer plate members 14 with the macroporous support members 40 inserted in the wells 34 thereof, are all suitably sealed together around their peri-pheries so as to form the assembled filtration module 10 as shown in Figures 1, 6 and 7. In its assembled form, the filtra-tion module 10 will be provided with a total of 6 spaced parallel suspension flow channels 130 arranged in upper and lower sets of three each. Each suspension flow channel 130 extends from one of the inlet flow passages 22 to the corresponding outlet flow passage 24, and is defined by a portion of the surface of ~( 1~.17(12~
the central core member 12, a portion of the surface of the upstxeam side of one of the microporous filtration membrane members 32, and the walls of one of the cut-out portions 30 of one of the gasket rnembers 28. The height of the suspension flow channels 130 is determined by the thickness of the gas~et members 28, and their length and width are determined by the length and width of the cut-out portions 30 of the gasket members 28. Thus, each of the suspension flow channels 130 will have a width across the surface of its membrane wall which gradually and uniformly increases along the length thereof from its inlet end to its outlet end, with the ratio of the width at the outlet end to that at the inlet end preferably being approximately 2:1.
The filtration module 10 as described above, may suitably be utilized for effecting separation of a cellular component-free liquid filtrate from a liquid suspension of blood cellular components in continuous laminar flow under pressure therethrough, such as, for example, separation of plasma from whole blood in a continuous flow plasmapheresis procedure, or removal of cryoprotective agent from a previously frozen, thawed blood cell suspension.
Details of the systems employed for carrying out these procedures are described in the copending Friedman et al, application referred to above and incorporated herein by reference.
When utilizing the filtration module 10 for effecting the filtrations in procedures of the type described above, the blood cell-containing liquid suspension is pumped into the suspension inlet port 16 of the filtration module 10, and flows through the inlet distributor channel 20 and the inlet flow )( 1~.17029 passages 22 into the inle-t ends of the suspension flow channels 130. As the liquid suspension flows through the suspension flow channels 130, cellular component-free liquid filtrate passes through the microporous filtration membrane members 32 and the macroporous support members 40 into the network of filtrate collector grooves 38. The filtrate then drains from the network of grooves 38 through the filtrate flow passages 42 into the filtrate collector channels 44 and then out of the filtration module through the filtrate outlet ports 46. The cellular component-containing fraction of the suspension leaving the outlet ends of the suspension flow channels 130 flows through the outlet flow passages 24 into the outlet collector channel 26 and then out of the filtration module through the suspension outlet port 18.
Due to the fact that each of the suspension flow channels 130 has a width across the surface of its membrane wall which gradually and uniformly increases along the length thereof from its inlet end to its outlet end, the membrane wall shear rate of the suspension flowing along the flow channel will gradually and uniformly vary along the length of the flow channel from a maximum value at its inlet end to a minimum value at its outlet end. This corresponds with the variation in the trans-membrane pressure along the length of the flow channel caused by the pressure drop through the system, and thereby facilitates proper correlation of the membrane wall shear rate with the transmembrane pressure conditions along the entire length of the suspension flow channel so as to insure optimal filtrate flux without damage to the cellular components.
A filtration module designed as described above was constructed with a total filtration area of 402 cm2, divided ~.1'7~3~
evenly among its six filtration flow channels. Each channel had a height of 0.051 cm, an effective filtration length of 40.6 cm, a widt:h of 1.1 cm at the inlet end of the filtration area and gradually and uniformly widening to 2.2 cm at the outlet end of the filtration area, and a filtration area of 67 cm2. Each of the two filtration membranes employed in the filtration module was a polycarbonate microporous membrane having an average pore diameter of 0.6 microns.
The filtration module constructed as above was utilized for separating plasma from whole blood under operating conditions providing an inlet suspension flow rate into the filtration module of 270 ml/min, a transmembrane pressure of 180 mm Hg and a membrane wall shear rate of 2000 sec 1 at the inlet end of the filtration flow channels, and a transmembrane pressure of 100 mm Hg and a membrane wall shear rate of 1000 sec 1 at the outlet end of the filtration flow channels. The procedure resulted in the collection of 500 ml of plasma in an operating time of approximately 30 minutes~ The plasma so collected was cell-free with an acceptably low level of hemoglobin content, indicating substantially hemolysis-free operation during the filtration.
The same filtration module was utilized for effecting the deglycerolization of a previously frozen, thawed preparation of red blood cells in a glycerol-containing electrolyte solution, under operating conditions providing an inlet suspension flow rate of 270 ml/min, a transmembrane pressure of 150 mm Hg and a membrane wall shear rate of 2000 sec 1 at the inlet end of the filtration flow channels, and a transmembrane pressure of 70 mm Hg and a membrane wall shear rate of 1000 sec at the outlet end of the filtration flow channels. The procedure resulted in a reduction of the glycerol concentration in the red blood cell suspension from a cryoprotectively effective level of approximately 1.4 moles per liter to a physiologically tolerable level of about 0.1 moles per liter in a period of approximately 30 minutes. The filtrate recovered contained glycerol, was cell-free, and had a free hemoglobin concentration not significantly greater than that of the original red blood cell suspension, indicating substantially hemolysis-free operation during the filtration.
X
The problems associated with the removal ofcryoprotective agents has been one of the major obstacles standing in the way of re extensive clinical use of frozen cells.
In the field of red cell freezing, various advantages have been cited for pro ting the use of this product. They include a possible reduction in hepatitis transmission, a reduction in transmission of undesirable antigens and antibodies, and most important, a prolonged storage period permitting accumulation of ~rare red cells" blood for autologous transfusion, and stockpiling for use during shortages. Current technology can be used to achieve these goals but a more simple and efficient system is needed.
Platelets frozen storage is desirable in order to reduce outdating and allow for provisions of ~matched~
or autologous cells. Techniques currently in use are not satisfactory and the microporous system may be suitable for such an application. Similarly, white cell storage is a problem ~nd transfusion of unfrozen products are still basically experimental. However, it is expected that utilization will increase, and that frozen storage will be needed for their efficient 2S management.
Another highly desirable blood processing procedure involving the separation of a liquid suspension of blood cellular components into a cellular component-containing fraction and a cellular component-free liquid fraction, is plasmapheresis. Plasmapheresis is defined as the process of removal of whole blood from the body of a blood donor by venesection, separation of its plasma portion, and reintroduction of the cellular portion into the donor's bloodstream. The cell-free plasma thus collected may either be used directly for patient care or ~urther processed into specific plasma derivatives for clinical use. The return of the cellular components to the donor provides this plasma 1117~2~
,~
collection procedure with the advantage that it enables donations by the donor at more frequent intervals. In addition to its use for plasma collection, plasmapheresis also has therapeutic implications in plasma exchange procedures for the treatment of various clinical disorders.
Currently, the most efficient and commonly employed techniques for carrying out the plasmapheresis procedure utilize "batchncentrifugation systems for effecting the separation of the cell-free plasma from the whole blood.
The most serious drawback with these currently used techriques is the relatively long period of donor time which they require, typically ranging from one to one-and-a-half hours or re for collecting 500 ml of cell-free pla~ma. Such long period of donor time tends tohave a detrimental effect upon the recruitment of volunteer donors and upon the overall cost-effectiveness of the plasmapheresis procedure.
Techniques for the separation of cell-free plasma from whole blood by filtration through a microporous membrane have previously been proposed. For example, in U. S. Patent No. 3,705,100, issued ~ecember 5, 1972, to Blatt, et al, there is disclosed a blood fractionating process and apparatus wherein whole blood is conducted in laminar flow across the surface of a microporous membrane along a flow path which is substantially parallel to the upstream side of the membrane under pressure conditions at the inlet and outlet ends of the flow path sufficient to maintain the laminar flow and to provide a filtration driving force from the upstream side to the downstream side of the membrane. Cell-free plasma is recovered as filtrate from the downstream side of the membrane, and the cellular component-containing fraction is recovered from the outlet end of the flow path. The patent teaches that one embodiment of the process and apparatus disclosed therein is capable of separating approximately 3.0 to 3.4 ml of plasma from a 10 ml sample of fresh blood of normal hematocrit in a filtering r ~117(~9 time of 15 to 20 minutes. While such filtering capacity may be adequate for the in vitro processing of relatively s~all amounts of plasma for subsequent physical, chemical or clinical analyses, it obviously would not be sufficient for practical utility in plasmapheresis, where the objective is to collect 500 ml of cell-free plasma in certainly no greater and preferably substan-tially less than the 60 to 90 minutes required by the standard plasmapheresis techniques.
In attempting to scale up the filtration process and apparatus disclosed in the Blatt, et al patent to a filtration capacity sufficient for practical utility in carrying out the plasmaphere~is procedure~ a number of interrelated factors must be taken into consideration.
First of all, in order to minimize the total required membrane area so that the resulting filtration dule will be reaRonably compact in size, and in order to-minimize the required period of donor time, it is most desirable to operate under conditions which will provide optimal filtrate flux, i.e., filtration rate per area of membrane.
Since, in certain cases, the filtrate flux will be governed primarily by the transmembrane pressure, i.e., the pressure differential between the upstream and downstream sides of the membrane providing the filtration driving force, the transmembrane pressure should be maintained sufficiently high so as to maximize the filtrate flux. However, too high a transmembrane pressure will cause the blood cellular components to be forced to the membrane surface and interact therewith, leading to irreversible damage or hemolysis of the cells or possibly even to plugging of the membrane pores.
Proper control of the transmembrane pressure so as to provide optimal filtration rate per area of membrane without causing damage to the cellular components is further complicated by the pressure drop from the inlet end to the outlet end of the blood flow path, which causes corresponding variations in the transmembrane pressure through the system. A relatively high pressure l.~i702~
drop could lead to a very low transmembrane pressure in the outlet region. Thus, in order to insure that the transmembrane pressure in the outlet region will be maintained sufficiently high for efficient operation, the transmembrane pressure in the inlet region must be correspondingly higher so as to compen-sate for the pressure drop thxough the system. Moreover, if the system is to be used for carrying out a truly continuous flow plasmapheresis procedure wherein the cellular component-containing fraction exiting from the outlet end of the filtra-tion flow path is directly reinfused into the donor's bloodstream,a further factor influencing the transmembrane pressure through the system is the requirement that the pressure at the outlet end of the filtration flow path be at least sufficient to over-come the sum of the return venous blood pressure and the pressure drop in the return needle and tubing assembly if an accessory blood pump is to be avoided.
An improvement in the filtration process is described in the aforementioned Blatt, et al patent. This improvement consists of controlling the membrane wall shear rate of the suspension along the filtration flow path so that such shear rate will be sufficiently high to cause axial migration of cells and inhibit interactions of the cellular components with the membrane surface at the particular transmembrane pressure conditions employed and sufficiently low so as not to itself induce mechanical lysis or damage to the cellular components.
It was found that by properly ,,.-, .. .
correlatin~ the membrane wa.ll shear rate with the particular set of transmembrane pressure conditions employed, it is possible to operate at transmembrane pressures providing optimal filtration - 5a -111~1)2~9 rate per area of membrane while at the same time inhibiting lysis-cau~ing interractions of the cellular components with the membrane surface which would othex-wise occur at lower membrane wall shear rates. As disclosed in said co-pending Friedman, et al application, such improvement enables the filtration process to be scaled up to a filtration capacity rendering it practical for use as the blood separation technique in a continuous flow plasmapheresis system, requiring a substantially shorter period of donor time than that required by the standard centrifugal techniques conventionally employed for this purpose; and furthermore `
broadens the applicability of the filtration process to also render it a relatively simple, efficient and economical technique for effecting removal of cryopro-tective agent from a previously frozen, thawed preparation of blood cells.
As disclosed in said co-pending Friedman, et al application, the membrane wall shear rate of the blood cell-containing liquid suspension along the filtration flow path is a function of both the inlet suspension flow rate and the filtration flow channel dimensions, increasing with increasing flow rates.and/or.decreasing flow cha~nel dimensions. Thus, once the operating membrane wall shear rate has been determined so as to be properly correlated with the transmembrane pressure conditions being employed to provide optimal filtrate flux without damage to the cellular components, such shear rate can be achieved by proper coordination of the inlet suspension flow rate with the filtration flow channel dimensions.
SUMMP.RY OF THE INVENTION
It is, accordingly, a primary object of the present invention to provide an improved filtration apparatus which is specifically designed for use in effectively carrying out the improved filtration process described and claimed in the aforementioned co-pending Friedman, .
1117~%9 et al applicatlon.
Another object of the invention is to provide a filtra-tion apparatus in accordance with the preceding object, which facilitates correlation of the membrane wall shear rate of the liquid suspension flowing therethrough with the transmembrane pressure conditions existing therein along the entire length of the filtration flow path.
The preferred embodiment of the filtration apparatus dis-closed herein has a reasonably compact size and a filtering capa-city sufficient to provide 500 ml of cell-free plasma filtrate from whole blood in approximately 30 minutes. The preferred appa-ratus has a filtering capacity sufficient to reduce the glycerol concentration in a unit of previously frozen, thawed glycerol-containing red blood cell preparation from a cryoprotectively effective level to a physiologically tolerable level in approxi-mately 30 minutes.
The present invention provides a filtration apparatus designed so that the membrane wall shear rate of a blood cell-containing liquid suspension in continuous laminar flow under pressure therethrough will vary along the length of the filtration flow path in the same manner as the transmembrane pressure, i.e.
from a maximum value at the inlet end of the filtration flow path to a minimum value at the outlet end thereof, thereby faci-litating correlation of the membrane wall shear rate with the transmembrane pressure conditions along the entire length of the filtration flow path so as to insure optimal filtrate flux with-out damage to the cellular components.
In accordance with the present invention there is provided in a filtration apparatus for effecting separation of a cellular component-free liquid filtrate from a liquid suspension of blood ~L17025'~
cellular components in continuous laminar flow under pressure through the apparatus by filtration through a microporous mem-brane which is permeable to blood proteins and impermeable to blood cellular components, comprising a housing means provided with a suspension inlet port and a suspension outlet poxt, the suspension inlet port leading into the inlet end of at least one continuous suspension flow channel which extends within the housing means and terminates at its outlet end in the suspension outlet port, each flow channel having one of its walls formed of a microporous filtration membrane disposed within the housing means, whereby the flow channel defines a filtration flow path along the surface of the upstream side of its membrane wall, the microporous filtration membrane being permeable to blood proteins and impermeable to blood cellular components and the housing means being further provided with a filtrate exit port disposed on the downstream side of the membrane wall, the improvement con-sisting of each of the flow channels having a width across the surface of its membrane wall which gradually and uniformly in-creases along the length thereof from its inlet end to its outlet end, each said channel being constructed and arranged so that the membrane wall shear rate of the suspension flowing along the filtration flow path will gradually and uniformly vary along the length of the flow channel from a maximum value at the inlet end to a minlmum value at the outlet end.
The filtration apparatus preferably includes a plurality of such flow channels of diverging width design in spaced parallel relation to each other across the surface of a single micro-porous filtration membrane, whereby spaced portions of the mem-brane constitute the respective membrane walls of the parallel flow channels. An inlet flow distributor means connects the res-0~9 pe~t~ nlet ellds of the parallel flow channels to the suspen-sion inlet port, and an outlet flow collector means connects the respect:ive outlet ends of the parallel flow channels to the sus-pension outIet port. A filtrate collector means disposed on the downstream side of the membrane walls collects and conducts to the filtrate exit port the filtrate passing through the respective membrane walls of the parallel flow channels. In its preferred embodiment, the filtration apparatus includes first and - 8a -0~
9 _ second microporou~ filtration m~mbranes in spaced parallel relation to each other, and fir~t and second sets of parallel spaced flow channels disposed between the two membranes, so that spaced portions of the first membrane constitute the respective membrane walls of the parallel flow channels of the first set, and spaced portions of the second membrane constitute the respective membrane walls of the parallel flow channels of the second set.
BRIEF DESCRIPTION OF THE DRAWINGS
Other features and advantages of the present invention will be apparent from the following detailed description of preferred embodiments accompanied by the attached drawings, in which: ¦
Figure 1 is a perspective view of a filtration module designed in accordance with the present invention in its assembled form;
Figure 2 is an exploded view in perspective with cutaway portions showing the component members of the filtration module of Figure l;
Figure 3 is an enlarged top view, partly in section, of the bottom outer plate member of the filtration module shown in Figure 2;
Figure 4 is a sectional view of the bottom outer plate member of the filtration module taken along the line 4-4 of Figure 3;
Figure 5 is a sectional view of the bottom outer plate member of the filtration module taken along the line 5-5 of Figure 3;
Figure 6 is an enlarged sectional view of the assembled filtration module taken along the line 6-6 of Figure l; and Figure 7 is an enlarged fragmented sectional view of the assembled filtration module taken along the line 7-7 of Figure 1.
)2~31 - 10 - i DESCRIPTION OF PREFERRED EMBODIMENTS
Referring now to Figure 1 of the drawings, a filtration module 10 in accordance with the present invention is shown in its preferred embodiment as 5 comprising a rectangular housing formed of a central core member 12 disposed between identical top and bottom outer plate members 14. The central core member 3 12 is provided at its one end with a suspension inlet port 16 leading into the housing, and at its other end 10 with a suspension outlet port 18 leading out of the housing.
Referring now to Figure 2, the suspension inlet port 16 is shown as leading into an inlet distributor channel 20 extending within the central core member 12 15 partially across its width. A plurality of inlet flow passages 22 spaced across the width of the central core member 12 lead from the inlet distributor channel 20 to the upper and lower surfaces of the central cor~
member 12. As shown, there are six such passages 22~
20 three leading to the upper surface and three to the lower surface of the central core member 12. At its opposite end, the central core member 12 is provided with six similarly arranged outlet flow passages 24 leading from its upper and lower surfacec into an outlet collector 25 channel 26 which extends within the central core member 12 partially across its width and leads into the suspension outlet port 18. The outlet flow passages 24 have a wider cross section than the inlet flow passages 22.
Identical upper and lower gasket members 28 are disposed over the upper and lower surfaces, respectively, of the central core member 12. The gasket members 28 are formed of a suitable elastomeric material, such as silicone rubber, and are provided with three lengthwise extending, transversely spaced, cut-out portions 30, each of which is positioned to extend over the surface of the central core member 12 from one of the inlet flow ,.
1~1702!~
passages 22 to the corresponding outlet flow passage 24. The width of each cut-out portion 30 gradually and uniformly increases along the length thereof from the inlet flow passage 22 to the outlet flow passage 24, its width at each end correspon-ding to the cross sectional width of the respective flow passage.
In the preferred embodiment of the filtration module in accordance with the present invention, the ratio of the width of the cut-out portion 30 at its outlet flow passage end to that at its inlet flow passage end is approximately 2:1.
The upper and lower gasket members 28 are covered, respectively, with identical upper and lower microporous filtra-tion membrane members 32. Such microporous membranes are known filter materials having holes of controlled shape and size running through their thickness and capable of effecting separation of very small particulate or molecular components from suspensions or solutions. Such microporous membranes are commercially available in various pore sizes. For example, poly-carbonate microporous membranes are commercially available under the trademark "Nuclepore" from the Nuclepore Corporation, and cellulosic ester microporous membranes are commercially available from Millipore Corporation. Suitable pore sizes found effective for filtering cell-free plasma from whole blood or cryoprotective agent from previously frozen, thawed blood cell suspensions, range broadly from about 0.2 to about 1.5 microns in diameter, and preferably from about 0.40 to about 0.60 microns in diameter.
The upper and lower microporous filtration membrane members 32 are covered, respectively, with the top and bottom outer plate members 14 which, in their surface facing the microporous filtration membrane member, are each provided with three lengthwise extending, transversely spaced wells 34, which correspond in shape, size and relative position with the cut-out portions 30 of the gasket members 28. The bottom wall of each well 34 is provided with a plurality of flat-surfaced ridges 36 form:Lng a network of filtrate collector grooves 38. Into each well 34 is inserted a macroporous support member 40, for example, formed of sintered polypropylene. The macroporous support members 40 are shaped and dirnensioned so as to rest upon the ridges 36 of its corresponding well 34 and completely fill the well above the network of filtrate collector grooves 38.
The structure of the outer plate members 14, without the macroporous support members 40 inserted therein, is more clearly shown in Figures 3 to 5. The network of filtrate collector grooves 38 formed by the ridges 36 on the bottom wall of each well 34 empties through a respective filtrate flow passage 42 into a filtrate collector channel 44 which extends transversely within the outer plate member 14 midway along its length. The filtrate collector channel 44 terminates in a filtrate outlet port 46.
The central core member 12, the upper and lower gasket members 28, the upper and lower microporous filtration membrane members 32, and the top and bottom outer plate members 14 with the macroporous support members 40 inserted in the wells 34 thereof, are all suitably sealed together around their peri-pheries so as to form the assembled filtration module 10 as shown in Figures 1, 6 and 7. In its assembled form, the filtra-tion module 10 will be provided with a total of 6 spaced parallel suspension flow channels 130 arranged in upper and lower sets of three each. Each suspension flow channel 130 extends from one of the inlet flow passages 22 to the corresponding outlet flow passage 24, and is defined by a portion of the surface of ~( 1~.17(12~
the central core member 12, a portion of the surface of the upstxeam side of one of the microporous filtration membrane members 32, and the walls of one of the cut-out portions 30 of one of the gasket rnembers 28. The height of the suspension flow channels 130 is determined by the thickness of the gas~et members 28, and their length and width are determined by the length and width of the cut-out portions 30 of the gasket members 28. Thus, each of the suspension flow channels 130 will have a width across the surface of its membrane wall which gradually and uniformly increases along the length thereof from its inlet end to its outlet end, with the ratio of the width at the outlet end to that at the inlet end preferably being approximately 2:1.
The filtration module 10 as described above, may suitably be utilized for effecting separation of a cellular component-free liquid filtrate from a liquid suspension of blood cellular components in continuous laminar flow under pressure therethrough, such as, for example, separation of plasma from whole blood in a continuous flow plasmapheresis procedure, or removal of cryoprotective agent from a previously frozen, thawed blood cell suspension.
Details of the systems employed for carrying out these procedures are described in the copending Friedman et al, application referred to above and incorporated herein by reference.
When utilizing the filtration module 10 for effecting the filtrations in procedures of the type described above, the blood cell-containing liquid suspension is pumped into the suspension inlet port 16 of the filtration module 10, and flows through the inlet distributor channel 20 and the inlet flow )( 1~.17029 passages 22 into the inle-t ends of the suspension flow channels 130. As the liquid suspension flows through the suspension flow channels 130, cellular component-free liquid filtrate passes through the microporous filtration membrane members 32 and the macroporous support members 40 into the network of filtrate collector grooves 38. The filtrate then drains from the network of grooves 38 through the filtrate flow passages 42 into the filtrate collector channels 44 and then out of the filtration module through the filtrate outlet ports 46. The cellular component-containing fraction of the suspension leaving the outlet ends of the suspension flow channels 130 flows through the outlet flow passages 24 into the outlet collector channel 26 and then out of the filtration module through the suspension outlet port 18.
Due to the fact that each of the suspension flow channels 130 has a width across the surface of its membrane wall which gradually and uniformly increases along the length thereof from its inlet end to its outlet end, the membrane wall shear rate of the suspension flowing along the flow channel will gradually and uniformly vary along the length of the flow channel from a maximum value at its inlet end to a minimum value at its outlet end. This corresponds with the variation in the trans-membrane pressure along the length of the flow channel caused by the pressure drop through the system, and thereby facilitates proper correlation of the membrane wall shear rate with the transmembrane pressure conditions along the entire length of the suspension flow channel so as to insure optimal filtrate flux without damage to the cellular components.
A filtration module designed as described above was constructed with a total filtration area of 402 cm2, divided ~.1'7~3~
evenly among its six filtration flow channels. Each channel had a height of 0.051 cm, an effective filtration length of 40.6 cm, a widt:h of 1.1 cm at the inlet end of the filtration area and gradually and uniformly widening to 2.2 cm at the outlet end of the filtration area, and a filtration area of 67 cm2. Each of the two filtration membranes employed in the filtration module was a polycarbonate microporous membrane having an average pore diameter of 0.6 microns.
The filtration module constructed as above was utilized for separating plasma from whole blood under operating conditions providing an inlet suspension flow rate into the filtration module of 270 ml/min, a transmembrane pressure of 180 mm Hg and a membrane wall shear rate of 2000 sec 1 at the inlet end of the filtration flow channels, and a transmembrane pressure of 100 mm Hg and a membrane wall shear rate of 1000 sec 1 at the outlet end of the filtration flow channels. The procedure resulted in the collection of 500 ml of plasma in an operating time of approximately 30 minutes~ The plasma so collected was cell-free with an acceptably low level of hemoglobin content, indicating substantially hemolysis-free operation during the filtration.
The same filtration module was utilized for effecting the deglycerolization of a previously frozen, thawed preparation of red blood cells in a glycerol-containing electrolyte solution, under operating conditions providing an inlet suspension flow rate of 270 ml/min, a transmembrane pressure of 150 mm Hg and a membrane wall shear rate of 2000 sec 1 at the inlet end of the filtration flow channels, and a transmembrane pressure of 70 mm Hg and a membrane wall shear rate of 1000 sec at the outlet end of the filtration flow channels. The procedure resulted in a reduction of the glycerol concentration in the red blood cell suspension from a cryoprotectively effective level of approximately 1.4 moles per liter to a physiologically tolerable level of about 0.1 moles per liter in a period of approximately 30 minutes. The filtrate recovered contained glycerol, was cell-free, and had a free hemoglobin concentration not significantly greater than that of the original red blood cell suspension, indicating substantially hemolysis-free operation during the filtration.
X
Claims (7)
1. In a filtration apparatus for effecting separation of a cellular component-free liquid filtrate from a liquid suspension of blood cellular components in continuous laminar flow under pressure through said apparatus by filtration through a micro-porous membrane which is permeable to blood proteins and imper-meable to blood cellular components, comprising a housing means provided with a suspension inlet port and a suspension outlet port, said suspension inlet port leading into the inlet end of at least one continuous suspension flow channel which extends within said housing means and terminates at its outlet end in said sus-pension outlet port, each flow channel having one of its walls formed of a microporous filtration membrane disposed within said housing means, whereby said flow channel defines a filtration flow path along the surface of the upstream side of its membrane wall, said microporous filtration membrane being permeable to blood proteins and impermeable to blood cellular components, and said housing means being further provided with a filtrate exit port disposed on the downstream side of said membrane wall, the improvement consisting of each of said flow channels having a width across the surface of its membrane wall which gradually and uniformly increases along the length thereof from its inlet end to its outlet end, each said channel being constructed and arrang-ed so that the membrane wall shear rate of the suspension flowing along said filtration flow path will gradually and uniformly vary along the length of said flow channel from a maximum value at said inlet end to a minimum value at said outlet end.
2. The filtration apparatus of Claim 1, wherein the ratio of said width of said flow channel at its outlet end to that at its inlet end is approximately 2:1.
3. The filtration apparatus of Claim 1, including a plurality of said flow channels in spaced parallel relation to each other across the surface of a single microporous filtration membrane, whereby spaced portions of said membrane constitute the respective membrane walls of said parallel flow channels.
4. The filtration apparatus of Claim 3, including an in-let flow distributor means connecting the respective inlet ends of said parallel flow channels to said suspension inlet port, and an outlet flow collector means connecting the respective outlet ends of said parallel flow channels to said suspension outlet port.
5. The filtration apparatus of Claim 4, including first and second microporous filtration membranes in spaced parallel relation to each other, and first and second sets of said parallel flow channels disposed between said two membranes, so that spaced portions of said first membrane constitute the respective membrane walls of said parallel flow channels of said first set, and spaced portions of said second membrane constitute the respective mem-brane walls of said parallel flow channels of said second set.
6. The filtration apparatus of claim 5, wherein each of said sets consists of three parallel flow channels.
7. The filtration apparatus of Claim 3, including a filtrate collector means disposed on the downstream side of said membrane walls for collecting and conducting to said filtrate exit port the filtrate passing through the respective membrane walls of said parallel flow channels.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US909,459 | 1978-05-25 | ||
| US05/909,459 US4212742A (en) | 1978-05-25 | 1978-05-25 | Filtration apparatus for separating blood cell-containing liquid suspensions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1117029A true CA1117029A (en) | 1982-01-26 |
Family
ID=25427261
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000328013A Expired CA1117029A (en) | 1978-05-25 | 1979-05-22 | Filtration apparatus for separating blood cell-containing liquid suspensions |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4212742A (en) |
| EP (1) | EP0016781B1 (en) |
| JP (1) | JPS55500375A (en) |
| CA (1) | CA1117029A (en) |
| DE (1) | DE2964597D1 (en) |
| WO (1) | WO1979001120A1 (en) |
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-
1978
- 1978-05-25 US US05/909,459 patent/US4212742A/en not_active Expired - Lifetime
-
1979
- 1979-05-22 CA CA000328013A patent/CA1117029A/en not_active Expired
- 1979-05-24 EP EP79900617A patent/EP0016781B1/en not_active Expired
- 1979-05-24 DE DE7979900617T patent/DE2964597D1/en not_active Expired
- 1979-05-24 WO PCT/US1979/000357 patent/WO1979001120A1/en unknown
- 1979-05-24 JP JP50090279A patent/JPS55500375A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP0016781A4 (en) | 1980-09-29 |
| US4212742A (en) | 1980-07-15 |
| EP0016781B1 (en) | 1983-01-26 |
| EP0016781A1 (en) | 1980-10-15 |
| JPS55500375A (en) | 1980-06-26 |
| WO1979001120A1 (en) | 1979-12-27 |
| DE2964597D1 (en) | 1983-03-03 |
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